The present invention, in some embodiments thereof, relates to anti-amphiregulin antibodies, compositions comprising same and uses thereof.
Growth factors and their cognate receptors mediate rapid responses to extracellular cues in a process tightly regulated by positive and negative feedback loops. Disturbance of this delicate balance is often implicated in disease development. An example of this scenario is provided by the Epidermal Growth Factor Receptor (EGFR) family of receptor tyrosine kinases (RTKs), and their EGF-like ligands. The family is comprised of four RTKs (EGFR/ERBB1/HER1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) and 11 ligands, polypeptides of the EGF/neuregulin (NRG) family. These ligands might be classified according to their affinity to EGFR, for example, EGF, transforming growth factor alpha (TGF-alpha), heparin-binding epidermal growth factor (HB-EGF), and betacellulin (BTC) are considered high-affinity ligands. By contrast, amphiregulin (AREG), epiregulin (EREG) and epigen (EPG) are considered low-affinity ligands.
It is well established that ligand binding to the extracellular region of EGFR promotes dimerization of the receptor and increases the activity of its intracellular kinase domain, leading to the activation of downstream signaling pathways. Following ligand binding, EGFR is rapidly internalized from the cell surface, which results in signal attenuation, either through the degradation of both receptor and ligand or the ligand alone. Interestingly, although high-affinity ligands stimulate a strong and robust response, the burst of activation is short lived due to potent negative feedback loops. However, under certain conditions the low-affinity ligands, including an engineered ligand, display relatively high mitogenic potency due to incompletely understood mechanisms. This phenomenon is also observed with the many EGFR ligands encoded by poxviruses. These viral ligands often display lower receptor binding affinity, as compared to their mammalian counterparts, but their biological activities are sometime more potent.
Of the low affinity ligands, AREG is being increasingly recognized for the key roles it plays in both normal and disease contexts. Human AREG is located on chromosome band 4q14.3 spanning approximately 10 kb of genomic DNA. AREG is flanked on the 5′ region by its family members EREG and EPG and on the 3′ region by another kin, BTC. The gene is composed of 6 exons that encode a 1.4 kb mRNA. The corresponding protein is synthesized as a 252 amino acid transmembrane precursor (pro-AREG), which is subjected to proteolytic cleavage within its ectodomain, thereby releasing a biologically active, soluble protein. This process is mediated by the tumor-necrosis factor-alpha converting enzyme (TACE), a member of the disintegrin and metalloproteinase family (also known as ADAM 17).
EGFR may be activated by AREG in several ways: autocrine or paracrine activation by the soluble form of AREG, a juxtacrine mode enabling the un-cleaved transmembrane form to activate EGFR, or by a newly described mode of signaling entailing AREG containing exosomes, that better enhance invasion of recipient cells in comparison to exosomes containing high affinity ligands.
AREG plays pivotal roles in mammary gland development, in oocyte maturation, as well as in branching and morphogenesis occurring within epithelial tissues, such as lung, prostate and kidney. Conversely, AREG has also been linked to the oncogenic process. AREG expression has been associated with worse prognosis of prostate, hepatocellular, pancreatic, breast, lung, colon, and head and neck tumors.
Additional background art includes:
U.S. Patent Application No. 2004/0210040 relates to amphiregulin (AR) antibodies and their use to treat cancer and psoriasis. Specifically, U.S. 2004/0210040 teaches anti-AR antibodies as well as pharmaceutical compositions comprising same and the use of same in inhibiting cancer cell (e.g. ovarian cancer) growth or psoriasis. The antibody of U.S. 2004/0210040 may be conjugated to an effector moiety such as a cytotoxic agent or may be administered in conjunction with a cytotoxic agent (e.g. chemotherapeutic agent).
U.S. Patent Application No. 2006/0246448 relates to inhibition of TACE or amphiregulin for the modulation of EGFR signal transactivation. Specifically, U.S. 2006/0246448 provides antibodies or antibody fragments directed against amphiregulin or TACE and the use of same for the treatment of hyperproliferative disorder such as cancer or psoriasis.
So et al. Febs Lett. 2014 588(21):3998-4007 teaches that increase in AREG induces ovarian cancer metastasis. Specifically, So et al. illustrate that AREG induces ovarian cancer cell invasion by down-regulating E-cadherin expression.